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PURPOSE: To report on the first-in-human phase I study of VIP152 (NCT02635672), a potent and highly selective cyclin-dependent kinase 9 (CDK9) inhibitor. PATIENTS AND METHODS: Adults with solid tumors or aggressive non-Hodgkin lymphoma who were refractory to or had exhausted all available therapies received VIP152 monotherapy as a 30-minute intravenous, once-weekly infusion, as escalating doses (5, 10, 15, 22.5, or 30 mg in 21-day cycles) until the MTD was determined. RESULTS: Thirty-seven patients received ≥ 1 VIP152 dose, with 30 mg identified as the MTD based on dose-limiting toxicity of grade 3/4 neutropenia. The most common adverse events were nausea and vomiting (75.7% and 56.8%, respectively), all of grade 1/2 severity. Of the most common events, grade 3/4 events occurring in > 1 patient were neutropenia (22%), anemia (11%), abdominal pain (8%), increased alkaline phosphatase (8%), and hyponatremia (8%). Day 1 exposure for the MTD exceeded the predicted minimum therapeutic exposure and reproducibly achieved maximal pathway modulation; no accumulation occurred after multiple doses. Seven of 30 patients with solid tumors had stable disease (including 9.5 and 16.8 months in individual patients with pancreatic cancer and salivary gland cancer, respectively), and 2 of 7 patients with high-grade B-cell lymphoma with MYC and BCL2/BCL6 translocations (HGL) achieved durable complete metabolic remission (ongoing at study discontinuation, after 3.7 and 2.3 years of treatment). CONCLUSIONS: VIP152 monotherapy, administered intravenously once weekly, demonstrated a favorable safety profile and evidence of clinical benefit in patients with advanced HGL and solid tumors.
Assuntos
Neoplasias , Neutropenia , Adulto , Quinase 9 Dependente de Ciclina , Relação Dose-Resposta a Droga , Humanos , Dose Máxima Tolerável , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/efeitos adversos , Resultado do TratamentoRESUMO
T-cell-mediated processes play an essential role in the pathogenesis of several inflammatory skin diseases such as atopic dermatitis, allergic contact dermatitis and psoriasis. The aim of this study was to investigate the role of the IL-2-inducible tyrosine kinase (Itk), an enzyme acting downstream of the T-cell receptor (TCR), in T-cell-dependent skin inflammation using three approaches. Itk knockout mice display significantly reduced inflammatory symptoms in mouse models of acute and subacute contact hypersensitivity (CHS) reactions. Systemic administration of a novel small molecule Itk inhibitor, Compound 44, created by chemical optimization of an initial high-throughput screening hit, inhibited Itk's activity with an IC50 in the nanomolar range. Compound 44 substantially reduced proinflammatory immune responses in vitro and in vivo after systemic administration in two acute CHS models. In addition, our data reveal that human Itk, comparable to its murine homologue, is expressed mainly in T cells and is increased in lesional skin from patients with atopic dermatitis and allergic contact dermatitis. Finally, silencing of Itk by RNA interference in primary human T cells efficiently blocks TCR-induced lymphokine secretion. In conclusion, Itk represents an interesting new target for the therapy of T-cell-mediated inflammatory skin diseases.
Assuntos
Dermatite/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Animais , Sequência de Bases , Dermatite/enzimologia , Dermatite/imunologia , Dermatite Alérgica de Contato/tratamento farmacológico , Dermatite Alérgica de Contato/enzimologia , Dermatite Alérgica de Contato/imunologia , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/enzimologia , Dermatite Atópica/imunologia , Dinitroclorobenzeno/imunologia , Dinitroclorobenzeno/toxicidade , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Feminino , Perfilação da Expressão Gênica , Humanos , Técnicas In Vitro , Tecido Linfoide/enzimologia , Tecido Linfoide/imunologia , Camundongos , Camundongos Knockout , Proteínas Tirosina Quinases/deficiência , Proteínas Tirosina Quinases/genética , Psoríase/tratamento farmacológico , Psoríase/enzimologia , Psoríase/imunologia , Interferência de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/genética , Proteínas Recombinantes de Fusão/antagonistas & inibidores , Proteínas Recombinantes de Fusão/genética , Linfócitos T/efeitos dos fármacos , Linfócitos T/enzimologia , Linfócitos T/imunologia , Regulação para CimaRESUMO
Acute myeloid leukemia (AML) is a devastating disease, with the majority of patients dying within a year of diagnosis. For patients with relapsed/refractory AML, the prognosis is particularly poor with currently available treatments. Although genetically heterogeneous, AML subtypes share a common differentiation arrest at hematopoietic progenitor stages. Overcoming this differentiation arrest has the potential to improve the long-term survival of patients, as is the case in acute promyelocytic leukemia (APL), which is characterized by a chromosomal translocation involving the retinoic acid receptor alpha gene. Treatment of APL with all-trans retinoic acid (ATRA) induces terminal differentiation and apoptosis of leukemic promyelocytes, resulting in cure rates of over 80%. Unfortunately, similarly efficacious differentiation therapies have, to date, been lacking outside of APL. Inhibition of dihydroorotate dehydrogenase (DHODH), a key enzyme in the de novo pyrimidine synthesis pathway, was recently reported to induce differentiation of diverse AML subtypes. In this report we describe the discovery and characterization of BAY 2402234 - a novel, potent, selective and orally bioavailable DHODH inhibitor that shows monotherapy efficacy and differentiation induction across multiple AML subtypes. Herein, we present the preclinical data that led to initiation of a phase I evaluation of this inhibitor in myeloid malignancies.
Assuntos
Antineoplásicos/farmacologia , Diferenciação Celular/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Di-Hidro-Orotato Desidrogenase , Feminino , Células HL-60 , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Pirimidinas/metabolismo , Células THP-1 , Translocação Genética/efeitos dos fármacosRESUMO
BACKGROUND: T cells play a central role in many inflammatory diseases, hence the identification and validation of T cell-specific target genes will increase the understanding of T cell function in pathologic inflammatory situations. RNA interference (RNAi), with its ability to induce specific gene silencing in mammalian cells, represents a powerful technology to investigate and validate the function of pharmaceutical target genes in vitro and in vivo. The aim of the present study was to systematically explore RNAi-mediated gene-silencing of known T cell-specific model signaling molecules in primary murine T cells in vitro and in vivo. RESULTS: We demonstrate that siRNA delivery and subsequent silencing of T cell specific genes is substantially increased, if murine T cells were activated prior siRNA transfection. Silencing of ZAP70, p56Lck as well as PLC-gamma1 protein expression resulted in impaired function of T cells in vitro. Furthermore, delayed type hypersensitivity (DTH) was ameliorated in vivo after adoptive transfer of ZAP70-silenced T cells. CONCLUSION: The combination of RNAi-mediated gene silencing and adoptive transfer of gene-silenced T cells, thus, may allow the identification and analysis of T cell-specific targets for therapeutic intervention. Additionally, this model system may represent an alternative to conventional time consuming and cost intensive gene targeting approaches.
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The lactate transporter SLC16A1/monocarboxylate transporter 1 (MCT1) plays a central role in tumor cell energy homeostasis. In a cell-based screen, we identified a novel class of MCT1 inhibitors, including BAY-8002, which potently suppress bidirectional lactate transport. We investigated the antiproliferative activity of BAY-8002 in a panel of 246 cancer cell lines and show that hematopoietic tumor cells, in particular diffuse large B-cell lymphoma cell lines, and subsets of solid tumor models are particularly sensitive to MCT1 inhibition. Associated markers of sensitivity were, among others, lack of MCT4 expression, low pleckstrin homology like domain family A member 2, and high pellino E3 ubiquitin protein ligase 1 expression. The antitumor effect of MCT1 inhibition was less pronounced on tumor xenografts, with tumor stasis being the maximal response. BAY-8002 significantly increased intratumor lactate levels and transiently modulated pyruvate levels. In order to address potential acquired resistance mechanisms to MCT1 inhibition, we generated MCT1 inhibitor-resistant cell lines and show that resistance can occur by upregulation of MCT4 even in the presence of sufficient oxygen, as well as by shifting energy generation toward oxidative phosphorylation. These findings provide insight into novel aspects of tumor response to MCT1 modulation and offer further rationale for patient selection in the clinical development of MCT1 inhibitors. Mol Cancer Ther; 17(11); 2285-96. ©2018 AACR.
Assuntos
Aminobenzoatos/farmacologia , Benzoatos/farmacologia , Biomarcadores Tumorais/metabolismo , Resistencia a Medicamentos Antineoplásicos , Transportadores de Ácidos Monocarboxílicos/antagonistas & inibidores , Sulfonas/farmacologia , Simportadores/antagonistas & inibidores , Aminobenzoatos/química , Animais , Benzoatos/química , Transporte Biológico/efeitos dos fármacos , Radioisótopos de Carbono , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fluorescência , Humanos , Concentração de Íons de Hidrogênio , Ácido Láctico/metabolismo , Camundongos SCID , Transportadores de Ácidos Monocarboxílicos/metabolismo , Proteínas Musculares/metabolismo , Pirimidinonas/farmacologia , Ácido Pirúvico/metabolismo , Sulfonas/química , Simportadores/metabolismo , Tiofenos/farmacologia , Resultado do Tratamento , Xenopus laevisRESUMO
Sagopilone, a fully synthetic epothilone, is a microtubule-stabilizing agent optimized for high in vitro and in vivo activity against a broad range of tumor models, including those resistant to paclitaxel and other systemic treatments. Sagopilone development is accompanied by translational research studies to evaluate the molecular mode of action, to recognize mechanisms leading to resistance, to identify predictive response biomarkers, and to establish a rationale for combination with different therapies. Here, we profiled sagopilone activity in breast cancer cell lines. To analyze the mechanisms of mitotic arrest and apoptosis and to identify additional targets and biomarkers, an siRNA-based RNAi drug modifier screen interrogating 300 genes was performed in four cancer cell lines. Defects of the spindle assembly checkpoint (SAC) were identified to cause resistance against sagopilone-induced mitotic arrest and apoptosis. Potential biomarkers for resistance could therefore be functional defects like polymorphisms or mutations in the SAC, particularly in the central SAC kinase BUB1B. Moreover, chromosomal heterogeneity and polyploidy are also potential biomarkers of sagopilone resistance since they imply an increased tolerance for aberrant mitosis. RNAi screening further demonstrated that the sagopilone-induced mitotic arrest can be enhanced by concomitant inhibition of mitotic kinesins, thus suggesting a potential combination therapy of sagopilone with a KIF2C (MCAK) kinesin inhibitor. However, the combination of sagopilone and inhibition of the prophase kinesin KIF11 (EG5) is antagonistic, indicating that the kinesin inhibitor has to be highly specific to bring about the required therapeutic benefit.